Binge behavior regulators

ABSTRACT

Methods and compositions utilizing 2-aminoindan derivatives collectively represented by Formula I as described and defined in the specification for regulating binge behavior, particularly binge drinking, are disclosed.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/167,576 filed on Oct. 23, 2018, which is a continuation of U.S.patent application Ser. No. 15/534,137 filed on Jun. 8, 2017, now U.S.Pat. No. 10,137,096, which is a National Phase of PCT Patent ApplicationNo. PCT/IL2015/051193 having International Filing Date of Dec. 9, 2015,which claims the benefit of priority under 35 USC § 119(e) of U.S.Provisional Patent Application Nos. 62/089,500 filed on Dec. 9, 2014 and62/089,504 filed on Dec. 9, 2014.

The contents of the above applications are all incorporated by referenceas if fully set forth herein in their entirety.

FIELD AND BACKGROUND OF THE INVENTION

The present invention, in some embodiments thereof, relates to bingebehavior, and more particularly, but not exclusively, to compositionsand methods for regulation of binge behavior such as binge drinking.

Binging or binge behavior is a non-controlled excessive behavior ofindulgence in a variety of activities such as eating, drinking, drugs,sweets, shopping, sexual conduct, and the like. It is now recognizedthat all types of binging are ways of dealing with negative emotionsthat are not rational or healthy.

Binge disorders are characterized by feelings of powerlessness, secrecy,shame, and social isolation. The occasional overindulgence becomes areal problem once a subject feels a need to binge in private, orschedule binges around (or instead of) work and social obligations.Binge eating is currently the most common eating disorder in adults,compulsive buying disorder (“shopaholism”) is increasing, and bingedrinking is widespread.

The causes of any type of binge behavior can fall into three categories:psychological, chemical, and sociocultural.

Most common psychological causes of binging are anxiety, stress, anddepression. While often binging is simply a way to numb unhappyfeelings, it can also be a symptom of an undiagnosed mental disorder.Depression, for example, can lead to low self-esteem, bodydissatisfaction, poor impulse control, and difficulty in managingfeelings—all of which can trigger a binge. Naturally the pain and guiltthat comes in the aftermath of a binge can trigger depression, which cantrigger another binge, and so on.

The brain releases dopamine (DA) when eating fat and sugar, whendrinking alcohol, or even when observing new things to buy. Once thebrain secretes DA during binges, binges can become like a physicaladdiction—one binges more and more because one craves the rush ofchemicals. Similarly, low levels of DA and serotonin can lead tocompulsive behavior (like bingeing) and depression.

Stress and anxiety can also make people binge by making them more proneto “reward seeking behavior”. Basically stress can cause loss ofperspective and prioritizing the nice feelings (“reward”) one getsduring a binge over the regret that inevitably comes later.

Sociocultural circumstances, such as the pressures of a culture thatemphasizes “coolness” through consumption, on a background of a poorsense of self-confidence, can also drive people to binges. The pressureto be perfect most often leads to anxiety and binge-like behavior.

First steps that may be taken by a person engaged in binge behavior,herein also referred to as a “binger”, in order to regulate bingebehavior and reduce the harmful effects thereof, include, for example,visiting a cognitive behavioral therapist and/or controlling bingesthrough continued therapy. Support groups like Alcoholics Anonymous,Overeaters Anonymous, or Debtors Anonymous are useful in many cases. Inserious cases of binge behavior, namely to the point where it causesdistress or financial, social, or physical harm, drug therapy isconsidered.

Alcohol is one of the favorite, commonly used, yet most dangerouspsychoactive substances that may lead to binge behavior upon excessive,uncontrolled consumption. Alcohol is consumed for several reasons, whichinclude quenching thirst, heating or cooling the drinker, for the tasteand because of the association alcoholic drinks have with other aspectsof life such as food and friendship. The psychological effects ofalcohol contribute to some of these reasons.

Many people with alcohol dependence find that sometimes they can controltheir intake and have just a couple of drinks. Whereas at other times,even though they set out with the intention of only having a couple ofdrinks, they lose control once they have had the first drink and thentake much more than they wanted to. Often this is in the form of a bingeor ‘bender’.

Alcohol consumption presents a growing problem worldwide, which somebelieve may have already overtaken tobacco in terms of overall healthand social care costs. Excessive and/or prolonged alcohol consumptionmay have some undesired physiological and psychological, includingshort-term, effects such as gastric irritation, anxiety disorders andother excitable states, and longer-term effects such as cirrhosis, fattyliver disease, cardiomyopathy and dementia. Alcohol consumption may leadto intoxication, which, in turn, can have serious consequences such asaccidents and uncontrolled violent behavior with subsequent medicalcomplications.

The toxic element in alcohol is ethanol, a two-carbon chain alcohol thathas a complex pharmacology. One of the current approaches to reduce orabolish the undesired effects of ethanol is to reduce the concentrationof alcohol in drinks, by means of, for example, dealcoholized beveragessuch as dealcoholized beer and wine.

Neuroscientific advances have greatly increased the understanding of thepharmaco-behavioral effects of various neurotransmitter systems in theacquisition and maintenance of binge behavior in general and alcoholdependence, in particular.

Ethanol is a pluripotent drug that affects many neurotransmittersystems. The sedative, ataxic and eventually terminal anaestheticactions of ethanol are thought to be mediated by interactions withprimary amino acid ionotropic receptors, especially GABA_(A) andglutamate receptors. Its major effect is on the endogenous inhibitoryeffect of the neurotransmitter γ-amino-butyric acid (GABA) by acting asan indirect agonist at the GABA_(A) receptor [Nutt, Br J Psychiatry 175:114-119, 1999], and possibly also the GABA_(B) receptor. Midbrain andcortical dopamine (DA) pathways mediate alcohol's rewarding effects.Thus, while alcohol consumption increases GABA receptor activity,midbrain DA neurons are inhibited and DA neurotransmission isfacilitated.

Alcohol is also an antagonist of the Non-N-methyl-D-aspartate (NMDA)type of glutamate receptors and hence reduces excitation in the centralnervous system. NMDA glutamate antagonists oppose GABA activity, therebydecreasing DA release. These actions explain many of the effects ofalcohol including its sedative, anxiolytic, amnestic and disinhibitingactions. Compensatory adaptive changes in these GABA and DA systems leadto a hyperexcitable state when alcohol intake is stopped, which explainsmany of the symptoms of withdrawal. The pleasurable effects associatedwith alcohol consumption as well as development and maintenance ofalcohol dependence are attributed, at least in part, to theseinteractions, but are assumed to also involve interactions withendogenous opioids (i.e., beta-endorphin), serotonin (5-HT), and otheramine systems.

In general, there are three types of treatments for addiction/dependenceon alcohol and/or drugs: withdrawal treatment, substitution therapy andabstinence-promoting therapy [Nutt et al. J. Psychopharmacol. 2012, Vol.26, No. 2, pp. 205-212].

The context of withdrawal treatment may vary, being sometimes elective(as a prior step in a patient's abstinence oriented therapy) or urgent,when some crisis has precipitated cessation of the addictive substance.Withdrawal reaction, if severe, might be life-threatening, as in severealcohol addiction.

Substitution therapy is defined as utilizing a substituting agent (i.e.,medication) that has one or more of the pharmacological effects ofalcohol, which are believed to be relevant to the addiction.Substituting agents are generally effective in assisting withdrawal fromalcohol abuse as they reduce craving and the desire to use alcohol. Inmany cases alcohol substitution therapy can be started once a decisionis made to stop consuming alcohol.

An important group of agents useful in substitution therapy for alcoholdependence are drugs that potentiate the actions of GABA, therebymimicking the actions of alcohol and substituting for it in withdrawal.

Such drugs include, for example, benzodiazepines, clomethiazole (asedative and hypnotic agent), tiagabine, vigabatrin (both areanticonvulsants), oxybate or baclofen, which target the GABAergicsystem. These drugs affect the GABA_(A) or GABA_(B) receptors eitherdirectly (e.g., clomethiazole and baclofen), or indirectly (e.g.,tiagabine that elevates GABA levels acutely by inhibiting GABA reuptake,or vigabatrin that elevates GABA levels chronically by irreversiblyinhibiting catabolism of GABA via inhibition of GABA transaminase).

Currently known substitution treatment is such that can substitute foralcohol but cannot be used along with alcohol. Some of the alcoholsubstitution agents, particularly the GABA_(B) receptors agonists, mighthave harmful effects when consumed together with alcohol (e.g. excessivesedation). This poses a severe limitation on the substitution treatment.A further concern associated with use of alcohol substitutents isdevelopment of dependence on these medications.

Abstinence promotion is the most widely recognized goal for addictiontreatment. In the strict sense, abstinence refers to not taking thesubstance of abuse, nor taking substituting treatments. Abstinencepromotion can be achieved, for example, by aversion.

Aversion is a long-established treatment for alcohol addiction. Thistreatment methodology is based on blocking alcohol metabolism to therebylead to accumulation of metabolic intermediates. This methodologyutilizes drugs such as disulfiram (Antabuse) and carbimide (Abstem),which are irreversible inhibitors of aldehyde dehydrogenase, and as suchtheir administration results in accumulation of acetaldehyde (a toxicintermediate in alcohol metabolism) when alcohol is consumed.Acetaldehyde accumulation is highly unpleasant, cause nausea and/orvomiting, headache and flushing. The concept behind the use of drugssuch as disulfiram is that the alcohol-dependent individual associatesdrinking with unpleasant adverse events. These adverse effects areintended to be off-putting and scary such that the alcoholic person isforced to refrain from drinking.

Anti-relapse drugs such as acamprosate, naltrexone, topiramate andgabapentin promote abstinence and reduce relapse risk through variousmechanisms. Acamprosate, a structural analogue of GABA, increasesabstinence rates and reduces the amount drunk in a lapse probably byattenuating conditioned responses to alcohol cues [Lingford-Hughes etal., Br Med Bull 96: 93-110, 2010]. Naltrexone(17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxymorphinan-6-onehydrochloride), an opioid antagonist, blocks the reinforcing effects ofalcohol by decreasing DA release in the nucleus accumbens, thus reducingcraving and heavy drinking, and increasing the percentage ofnon-drinking days, however, not necessarily enhancing abstinence.Topiramate (2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranosesulfamate), a GABA/glutamate modulator, is thought to have multiplemechanisms of action, amongst which is enhanced GABA inhibition thatresults in decreased DA facilitation in the midbrain [Johnson, 2004,Alcohol. Clin. Exp. Res., 28:1137-1144]. Gabapentin reduces glutamateand increases GABA neurotransmission in the brain. Theoretically,therefore, the unique pharmacology of these medications is well suitedto the treatment of alcohol dependence or withdrawal and could normalizethe brain dysregulation seen during the early abstinence period.

Dopamine receptors (DRs) are a class of G protein-coupled receptors thatare prominent in the central nervous system (CNS). Dopamine receptorsare implicated in many neurological processes, including motivation,pleasure, cognition, memory, learning, and fine motor control, as wellas modulation of neuroendocrine signaling. Abnormal dopamine receptorsignaling and dopaminergic nerve function is implicated in severalneuropsychiatric disorders. Thus, dopamine receptors are commonneurologic drug targets. Antipsychotics are often DRs antagonists, whilepsychostimulants are typically indirect agonists of DRs. It is believedthat fluctuating dopamine (DA) levels contribute to craving, which leadsin turn to relapse in abstinent alcoholics.

Antipsychotics (e.g., neuroleptics) that regulate DA occupancy atDRD2/DRD3, possibly causing an up-regulation of these receptors, havebeen hypothesized as associated with reduced positive symptoms ofschizophrenia as well as reduced alcohol craving. The antipsychoticsdrugs haloperidol, tiapride, olanzapine, clozapine and aripiprazole haveall demonstrated various degrees of efficacy in reducing craving andalcohol consumption or increasing abstinence. However, the risksassociated with the side effects of typical or atypical neurolepticshave outweighed the benefits for using DA antagonists as a treatment ofalcoholism.

Compounds derived from 2-aminoindan have been shown to selectively bindto the dopamine D3 receptor. U.S. Pat. No. 5,708,018 discloses some2-aminoindan derivatives, and hypothesizes that these 2-aminoindanderivatives may be useful in treating CNS disorders associated withdopamine D3 receptor.

Various types of combination therapies have been used in an attempt totreat and prevent excessive alcohol drinking and dependence thereon. Forexample, European (EP) Patent No. 2556830 discloses combination therapyfor the treatment of addictive use of alcohol and increase of abstinencerate, comprising the use of at least two anti-alcohol drugs such astopiramate, naltrexone and/or ondansetron(9-methyl-3-[(2-methyl-1H-inudazol-1-yl)methyl]-1,2,3,9-tetrahydrocarbazol-4-one),for reducing the frequency of alcohol consumption or the quantity ofalcohol consumed. Anton et al. [2006, J. Am. Med. Assoc., 295:2003-2017]teaches combined pharmacotherapies (naltrexone and acamprosate) withbehavioral therapy. However, current evidence for the usefulness ofcombination pharmacotherapy is lacking.

Harm reduction relates to new approaches (available or underinvestigation) that do not fall easily into current terminology, andinclude any intervention that reduces the harms of drugs/alcohol use,including social measures and medications.

In alcohol consumption, and particularly in excessive intake and alcoholdependence, the harm reduction approach is aimed at reducing harmfullevels of drinking mainly by the use of drugs that reduce the amount ofalcohol drunk in a single drinking session, and possibly the number ofdrinking sessions [Nutt et al. J. Psychopharmacol. 2012. Vol. 26. No. 2,pp. 205-212]. Harm reduction is thus obtained by the use ofdrink-regulating agents, also termed herein and in the art as bingeregulators, drinking regulators, drinking restrictors, drinking-controlagents, anti-bingeing agents or self-control drugs [Nutt et al. J.Psychopharmacol, 2012, Vol. 26, No. 2, pp. 205-212].

The feasibility of interfering with the destructive pattern of bingedrinking came from studies with the opioid antagonists naltrexone andnalmefene when being used as part of a relapse prevention abstinenceprogram. It was found that when used to assist abstinence, naltrexone,instead, was more effective at preventing a lapse becoming a fullrelapse, than in promoting complete abstinence [Rosner et al., J.Psychopharmacol 22: 11-23, 2008]. The mechanism seems to relate toendorphin: an important initial action of alcohol is to releaseendorphins, which then drive the dependence-prone person to drink moreand more alcohol—so called loss-of-control drinking. Naltrexone andnalmefene block the endorphin effects and so lessen the risk of thedrinking being leading to relapse. It was hypothesized that in this waythese drugs lead to a lower, more regulated level of drinking with fewerbinges/benders. When taken in a targeted (as required) fashion, that is,only on those days when the patient felt at risk of drinking, thesedrugs substantially reduced drinking than when taken each day[Karhuvaara et al., Alcohol Clin Exp Res 31: 1179-1187, 2007].

Nalmefene is marketed in Europe under the trade name Selincro. The UKNational Institute for Health and Care Excellence (Nice) recommended thedrug's use after trials showed it cut drinking by 61% over six monthswhen used with counseling.

Nalmefene is administered orally as a pill once a day and is taken whenpeople feel the urge to drink. It works by blocking the endorphineffects which gives drinkers pleasure from alcohol, stopping them fromwanting more than one drink. Men would qualify to receive the treatmentif they consume 7.5 units of alcohol per day (around three to four pintsof standard strength lager (beer)), and women would qualify if theyconsume five units of alcohol a day, which amounts to around half abottle of wine.

Nalmefene is now the only licensed medication which is aimed at reducingdrinking rather than totally refrain from drinking. However, severealcoholics and those who are not recognized as alcoholics or even asbinger, are not eligible for the drug. Moreover, nalmefene cannot beconsumed together with alcohol.

Additional Background art includes Koob, 2003, Alcohol Clin. Exp. Res.,27:232-243; and Weiss and Porrino, 2002, J. Neurosci., 22:3332-3337.

SUMMARY OF THE INVENTION

The need for binge regulation, such as regulation of alcoholic bingingis yet unmet.

The idea that drugs might control or regulate binge behavior is arelatively new approach.

Binge regulators such as regulators of binge drinking present analternative strategy to abstinence-promotion and target a group ofalcohol-dependent patients who often are not interested in abstinencebut rather are in need of better control on their alcohol consumption.

The present invention discloses compositions comprising a derivative of2-aminoindan, as described herein, useful as binge regulators or bingemitigation agents that impart a feeling of satisfaction, satiety orcontentedness and thereby regulate (e.g., discourage) binge behaviorsuch as binge drinking.

According to an aspect of some embodiments of the present inventionthere is provided a method of regulating binge behavior, the methodcomprising administering to a subject in need thereof a compoundrepresented by Formula I:

wherein:

each of R₁ and R₂ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₄)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl,aryl, heteroaryl, heteroalicyclic, —O(C₁-C₆)alkyl, OH, —OS(═O)₂CF₃,—OS(═O)₂—(C₁-C₆)alkyl, —S(═O)R₅, —CO₂R₅, —CONR₅R₆, —COR₅, —CF₃, CN,—SRS, —SO₂NR₅R₆, —SO₂R₅, —OCO—(C₁-C₆)alkyl, —NCO—(C₁-C₆)alkyl,—CH₂O—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-OH, and halogen, or, alternatively, R₁and R₂ together with two or more of the phenyl carbon atoms form aX₁—(CR₅R₆)_(m)—X₂— ring, wherein each of X₁ and X₂ is independentlyselected from O, NH or S and m is 1, 2, 3, or 4;

each of R₃ and R₄ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈) cycloalkyl, and—(CH₂)_(p)-thienyl, wherein p is 1, 2, 3, or 4, or alternatively, R₃ andR₄ are joined together to form a heterocylic ring (heteroalicyclic orheteroaryl) containing the nitrogen atom to which they are attached; and

each of R₅ and R₆ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl and aryl,

thereby regulating the binge behavior.

According to an aspect of some embodiments of the present inventionthere is provided a compound represented by Formula I, as describedherein in any one of the respective embodiments, for use in regulatingbinge behavior.

According to an aspect of some embodiments of the present inventionthere is provided a use of a compound represented by Formula I, asdescribed herein in any one of the respective embodiments, for thepreparation of a medicament for regulating binge behavior.

According to some of any of the embodiments of the present invention,the binge behavior is associated with alcohol consumption, eating,smoking, shopping or sexual conduct.

According to some of any of the embodiments of the present invention,the binge behavior is binge drinking.

According to an aspect of some embodiments of the present inventionthere is provided a method of regulating consumption of an alcoholicbeverage, the method comprising administering to a subject in needthereof a compound represented by Formula I, or a composition comprisingsame, as described herein in any one of the respective embodiments,thereby regulating the consumption of an alcoholic beverage.

According to an aspect of some embodiments of the present inventionthere is provided a compound represented by Formula I, as describedherein in any one of the respective embodiments, for use in regulatingconsumption of an alcoholic beverage.

According to an aspect of some embodiments of the present inventionthere is provided a use of a compound represented by Formula I, asdescribed herein in any one of the respective embodiments, in thepreparation of a medicament for regulating consumption of an alcoholicbeverage.

According to some of any of the embodiments of the present invention,the consumption of alcoholic beverage is associated with binge drinking.

According to some of any of the embodiments of the present invention,the method or compound or use is for reducing an amount of alcoholconsumption during a drinking session.

According to some of any of the embodiments of the present invention,the compound or the composition is administered before, simultaneouslywith, or subsequent to consumption of an alcoholic beverage.

According to some of any of the embodiments of the present invention,the compound is administered simultaneously with an alcoholic beverage.

According to some of any of the embodiments of the present invention,the compound is being incorporated in the alcoholic beverage.

According to some of any of the embodiments of the present invention,the amount of the compound is in the range selected from 0.15 mg/ml to0.60 mg/ml, 0.15 mg/ml to 0.50 mg/ml, 0.15 to 0.40 mg/ml, 0.18 to 0.50mg/ml, 0.18 to 0.40 mg/ml, 0.20 to 0.40 mg/ml, 0.20 to 0.30 mg/ml, 0.20to 0.25 mg/ml, or 0.20 to 0.23 mg/ml.

According to some of any of the embodiments of the present invention,for a compound represented by Formula I, each of R₁ and R₂, eachindependently is selected from the group consisting of H, (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, aryl, —OCH₃, OH,—OSO₂CF₃, —OSO₂CH₃, —SOR₅, —CO₂R₅, —CONR₅R₆, —COR₅, —CF₃, —CN, —SRS,—SO₂NR₅R₆, —SO₂R₅, —CH₂—OH, halogen, phthalimidyl, thiophenyl, pyrrolyl,pyrrolinyl, and oxazolyl, or, alternatively, R₁ and R₂ together with twoor more of the phenyl carbon atoms form a —O(CH₂)_(m)O— ring, wherein mis 1 or 2;

R₃ and R₄ are joined together to form a heterocylic ring containing 4 to8 carbon atoms with the nitrogen atom to which they are attached; and

Each of R₅ and R₆ is independently selected from the group consisting ofH, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₃-C₈) cycloalkyl.

According to some of any of the embodiments of the present invention, atleast one of R₃ and R₄ is H.

According to some of any of the embodiments of the present invention, R₃or R₄ is propyl.

According to some of any of the embodiments of the present invention,each of R₁ and R₂ is independently H, —OCH₃, or —OSO₂CF₃, or R₁ and R₂together with two or more of the phenyl carbon atom form a —O(CH₂)_(m)O—ring, wherein m is 1 or 2.

According to some of any of the embodiments of the present invention,the compound of Formula I is selected from: 5-methoxy-2-aminoindan; and5,6-dimethoxy-2-aminoindan.

According to some of any of the embodiments of the present invention,the compound forms a part of a composition which further comprises apharmaceutically acceptable carrier.

According to some of any of the embodiments of the present invention,the compound or composition are formulated for oral administration.

According to some of any of the embodiments of the present invention,the composition is in a form of a free-flowing powder, a tablet, acapsule, a lozenge, a liquid, a liquid concentrate or a syrup.

According to some of any of the embodiments of the present invention,the composition is a unit dosage form composition.

According to some of any of the embodiments of the present invention, anamount of the compound in the unit dosage form ranges from 30 mg to 130mg.

According to some of any of the embodiments of the present invention,the amount of the compound is 70 mg.

According to some of any of the embodiments of the present invention,the compound or composition is administered to a subject orally.

Unless otherwise defined, all technical and/or scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods and/or materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates to bingebehavior, and more particularly, but not exclusively, to compositionsand methods for regulation of binge behavior, such binge drinking.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not necessarily limited in itsapplication to the details set forth in the following description orexemplified by the Examples. The invention is capable of otherembodiments or of being practiced or carried out in various ways.

A discussed hereinabove, different binge behaviors have similar causes,whether it's drinking, eating, smoking, shopping, or sexual conduct, andthat all types of bingeing are ways of dealing with negative emotionsthat are not rational or healthy.

The terms “binge”, “binge behavior”, “binge disorder”, “bingeing” and“bingeing behavior” as used herein are interchangeable and relate tonon-controlled excessive behavior of indulgence in a variety ofactivities such as eating, drinking, smoking, drugs use, shopping,sexual conduct, and the like. Binge behavior includes intensive, shortepisodes of overuse and over consumption of food, alcohol, smokingproducts, drugs, sweets, sex and the like. Bingeing behaviors arecompulsive in style, intensity, habituation, history, motivation, anddifficulty to control and remediate. “Compulsive behavior”, as usedherein refers to driven behaviors which are often influenced bysubconscious desires and motives, as well as strong, uncontrollable,hard-to-tame actions and behaviors which have a predictable pattern.

The present inventor has uncovered that when certain psychoactivecompounds that up-regulate the dopamine receptors D2 and D3 in the CNSare consumed together with alcoholic beverages, for example, an amountof 70 mg of powder form of an antipsychotic that regulates DA occupancyat dopamine receptors, dissolved in at least one whiskey shot or in atleast one beer glass during a night of drinking, the added compoundimparts a feeling of satisfaction, satiety or contentedness which haltor discourage the drinker from consuming more alcohol, therebydiscouraging binge drinking behavior.

Mixing these compounds in certain amounts of liquid does not impair theinebriating feeling of consuming beer or wine or a spirit in theiruser's experience. However, consuming these compounds imparts to theconsumer a feeling of satisfaction, satiety or contentedness whichdiscourages binge behavior. These compounds, although intoxicating in away similar to alcohol (at least at low dosages) and even having someanxiolytic and sedative effects, are not harmful in terms of motor,cognitive and addictive effects attributed to consumption of alcoholicbeverages.

Embodiments of the present invention therefore relate to a method forbinge mitigation utilizing certain aminoindan derivatives known as DRD2and/or DRD3 regulators, which provide the person engaged in a bingingbehavior such as binge drinking, binge eating, binge smoking and thelike, psychotropic effects such as a feeling of satisfaction, satiety orcontentedness which discourages, moderate or halt the binging.

Embodiments of the present invention concern controlling, or regulating,binge behavior, such as, but not limited to, binge drinking, whileutilizing aminoindan derivatives, more particularly 2-aminoindanderivatives, collectively represented by Formula I as presented herein.

Exemplary embodiments of the present invention are of alcoholicbeverages such as 300 ml beer or wine or 100 ml whiskey which are mixedwith 30-130 mg of a 2-aminoindan derivative and consumed during adrinking session.

According to an aspect of some embodiments of the present invention,there is provided a method of regulating binge behavior in a subject inneed thereof, which is effected by administering to the subject anaminoindan derivative, more particularly, a 2-aminoindan derivative,represented by Formula I as described herein.

A 2-aminoindan derivative as described herein is referred to hereinmainly as a “binge regulating agent”, “binge mitigating agent” or “bingeregulator”, but also as “drinking regulator”, “drinking restrictor”,“drinking-control agent”, “anti-bingeing agent” or “self-control drug”.

In the context of the present embodiments, regulating binge behavior isalso referred to herein interchangeably as controlling or mitigatingbinge behavior, or as treating a binge disorder, and concernscontrolling the excessive, compulsive behavior of indulgence, by, forexample, reducing the uncontrollable need of a binged person to consumefood, alcohol, sex, tobacco, sweets or to shop, or any other subject ofexcessive compulsive consumption (binge's subject). Regulating bingebehavior therefore relates to restraining or moderating the compulsivebehavior as defined herein, namely, restraining or moderating thestrong, uncontrollable, hard-to-tame actions and behaviors which have apredictable pattern. In some embodiments, regulating binge behavior isconsidered as treating a binge disorder, as described herein.

In some of any of the embodiments described herein, regulating bingebehavior describes reducing a consumption of the binge's subject (e.g.,alcoholic drink, food, smoking or tobacco product, drug, sweets, sexualconduct, shopping) during a binge episode and/or in reducing theoccurrence of episodes of binge behavior during a certain time period.In some of these embodiments, consumption is reduced by at least 10%, orat least 20%, or at least 30, or at least 40%, or at least 50%, and evenby 60%, 70% or more, compared to episodes without administering thebinge regulating agent described herein. Alternatively, or in addition,the number of episodes of binge behavior during a certain time period(e.g., a week or a month or a year) is reduced by at least 10%, or atleast 20%, or at least 30%, or at least 40%, or at least 50%, and evenby 60%, 70% or more.

Controlling a binge behavior may result in substantially reducing theharmful effects associated with, and/or harmful consequences of, a bingebehavior.

Regulating binge behavior as described herein can therefore be used forharm reduction.

“Harm reduction”, in a broad interpretation refers to any interventionthat reduces the harmful effects of bingeing, as defined herein. Harmreduction includes social measures as well as medications to ameliorate,reduce, moderate or prevent harmful effects and consequences associatedwith a compulsive binge behavior, such as harmful mental, psychological,physiological, economical, social and cultural effects exhibited by asubject engaged in a binge behavior. Harm reduction is obtainable, forexample, by regulating binge behavior.

A subject in need of regulating a binge behavior is typically a subjectthat experiences episodes of over consumption of the binge's subject(e.g., food, alcohol, smoking, drug use, sweets, sex, shopping, etc.),either on a regular basis, for example, more than once a week, oroccasionally, or even rarely, for example once or twice a year,depending on the severity of the binges. Blackout drinkers, for example,that experience a blackout when consuming alcohol even as rarely astwice per year are defined herein as subjects is need of regulatingbinge drinking. Determining a subject in need of regulating bingebehavior can be made, in some cases, according to national orinternational standards, or by acceptable evaluations by healthprofessionals (e.g., physicians, psychologists, cognitive therapists,social workers, nutritionists, etc., depending on the binge disorder).

In some of any of the embodiments of the present invention, bingebehavior is associated with alcohol consumption, tobacco consumption,eating, shopping and/or sexual conduct.

In some of any of the embodiments of the present invention, the bingeregulator represented by Formula I as described herein is utilized(e.g., administered, or self-administered), either before,simultaneously with, or subsequent to consumption of a binge's subject.For example, it is utilized before, during or subsequent to a meal orother eating event, a drinking session or other drinking event, ashopping episode, and/or in accordance with a subject's habitudes, forexample, in accordance with times or events of binge smoking, binge sex,binge shopping, etc.

An effective amount of binge mitigating agent is an amount that whenadministered to the subject regulates binge behavior, as describedherein.

The effective amount depends inter alia on the type of binge behavior,its severity, its occurrence, and on several other factors, and can bedetermined by a health professional and/or by the subject himself.

In exemplary embodiments, the effective amount that is administered to asubject to regulate a single episode of binge behavior is in a range offrom 30 mg to 800 mg.

The effective amount can be administered to the subject at once, in asingle dose, or be divided to several doses over the time of bingeing orcan be administered per day over a period of time, per a desired regimenas follows.

Depending on the type and severity of the binge disorder, the bingemitigation agent can be administered in a chronic regimen (namely, everyday, every other day, twice a week, once a week, or twice or more aday), or “per demand”, namely, before, during or subsequent a bingebehavior, as described herein.

Administering the binge regulating agent can be made according to adosage and/or regimen recommended by a health professional or can beself-administering by the subject per the subject's demands (forexample, when a subject determines he is in need of regulating a bingebehavior).

According to some of any of the embodiments described herein, the methodof regulating binge behavior is for regulating binge drinking.

In the context of embodiments of the present invention, regulating bingedrinking relates to controlling the excessive behavior of indulgence indrinking alcoholic beverages. For example, regulating binge drinking mayinvolve reducing the amount of alcohol consumed in a drinking sessionand/or the number of drinking sessions in a week, per the embodimentsdescribed hereinabove.

Regulating binge drinking provides restraining or moderating thecompulsive uncontrollable, behavior associated with binge drinkingthereby reducing the harmful consequences associated with excessivealcohol consumption, while not impairing the psychological and socialpleasures associated with the drinking.

The phrase “binge drinking” or “binge drinking disorder” as used hereinis determined according national or international definitions as definedby regulation authorities, for example, in line with the definition ofbinge drinking used by the National Health Service (NHS) and theNational Office of Statistics in the United Kingdom (UK), andcorresponding services, offices and/or authorities in other countries.The definition of binge drinking used by NHS and the National Office ofStatistics describes it as drinking more than double the lower riskguidelines for alcohol in one drinking session, wherein the guidelinesadvise that people should not regularly drink more than the lower riskguidelines of 3-4 units of alcohol for men (equivalent to a pint and ahalf of 4% beer (about 852 ml)) and 2-3 units of alcohol for women(equivalent to a 175 ml glass of wine). “Regularly” means drinking everyday or most days of the week.

“One unit of alcohol” as defined herein and acceptable in the art is 10ml of pure alcohol. It takes an average adult around an hour to processthis so that there's none left in the bloodstream, although this variesfrom person to person.

In some embodiments, binge drinking for men, therefore, is regularlydrinking more than 8 units of alcohol—or about three pints of strongbeer. For women, it's regularly drinking more than 6 units of alcohol,equivalent to 2¼ pints of strong beer or two large glasses of wine.

In an aspect of some embodiments of the present invention, there isprovided a method of regulating consumption of an alcoholic beverage ina subject in need thereof, the method being effected by administering tothe subject a compound represented by Formula I as described herein. Insome embodiments, the consumption of alcohol beverages is excessive anduncontrolled as in binge drinking. In some embodiments, the subject isdetermined as having a binge drinking disorder, as defined herein. Insome of these embodiments, the method provided herein is for regulatingbinge drinking or treating a binge drinking disorder in a subject inneed thereof.

In some embodiments, the method provided herein is for reducing alcoholconsumption in a non-binger subject who wishes to control his alcoholconsumption, for example, under certain circumstances (for example,during a specific event or time point).

The term “binge drinking regulation” in a broad interpretation refers tocontrolling the excessive, uncontrolled consumption of alcoholicbeverages. Regulating binge drinking relates to reducing the amount ofalcohol consumed in a drinking session and/or reducing the number ofdrinking sessions.

In the context of embodiments of the present invention, binge drinkingregulation relates to imparting a feeling of satisfaction, satiety orcontentedness which discourages binge drinking. Binge drinkingregulation as practiced in embodiments of the present invention effectsa true harm reduction utility by discouraging binge drinking in a waythat is easy to implement (by drinking) and non harmful (pendingtoxicological validation) to the drinker.

In some of any of the embodiments of the present invention, the bingeregulator represented by Formula I as described herein is administeredeither before, simultaneously with, or subsequent to consumption of analcoholic beverage.

An effective amount of a binge regulating agent in the context of theseembodiments of the present invention is an amount that when consumedeither before, simultaneously with or subsequently after consumption ofan alcoholic beverage, will regulate (e.g., discourage) binge drinking.

The overall amount of the binge regulating agent that when administeredbefore, simultaneously with or subsequently following, a binge drinkingepisode, and is effective in discouraging immediate (soon to happen),ongoing or continued binge drinking, depends on the mental and physicalsituation of the subject in need of binge drinking mitigation. In someembodiments, the effective amount, namely the total amount that wouldprevent, moderate, halt or discourage binge drinking in a single episodeof binge drinking (e.g., in a single drinking session) is in a range offrom 30 mg to 400 mg, and sometimes even up to 800 mg.

As discussed in further detail herein, the effective amount can beadministered to the subject at once, in a single dose, or be divided toseveral doses administered during a binge drinking episode (e.g., adrinking session).

According to some embodiments of the this aspect of the presentinvention, unit dosage forms of a binge regulating agent as representedby Formula I as described herein are utilized, whereby each unit dosageform comprises one or more derivatives of a 2-aminoindan of Formula I asdescribed herein in an amount within a range of from 30 mg to 130 mg,from 30 mg to 120 mg, from 40 mg to 120 mg, from 40 mg to 110 mg, from50 mg to 110 mg, from 50 mg to 100 mg, from 50 mg to 90 mg, from 60 mgto 90 mg, or from 60 mg to 80 mg, and any intermediates therebetween.

In exemplary embodiments, a unit dosage form contains 70 mg or 80 mg ofa binge regulating agent as described herein.

In exemplary embodiments, 1-10 such unit dosage forms are administeredto the subject during a single drinking session.

In exemplary embodiments, administration of the amount of 70 mg ofdrinking regulator selected form Compound 1 or Compound 2 describedherein reduced the amount of beer drunk in a binge session from 1.5liter to 0.5 liter, or the amount of wine drunk in a binge session from1000 ml to 250 ml.

In some embodiments, the binge regulating agent represented by Formula Iand the alcoholic beverage are consumed simultaneously, for example, byintroducing (e.g., dissolving or mixing) the binge regulating agent withthe alcoholic beverage.

In embodiments wherein the binge regulating agent is being mixed with abeverage, for example an alcoholic beverage, the amount of said bingeregulating agent is in a range selected from 0.15 mg/ml to 0.60 mg/ml,0.15 mg/ml to 0.50 mg/ml, 0.15 to 0.40 mg/ml, 0.18 to 0.50 mg/ml, 0.18to 0.40 mg/ml, 0.20 to 0.40 mg/ml, 0.20 to 0.30 mg/ml, 0.20 to 0.25mg/ml, or 0.20 to 0.23 mg/ml.

In some embodiments, the drinker himself mixes or dissolves the drinkingregulating agent with the alcoholic drink, such that the bingeregulating agent is self-administered. In some other embodiments, thealcoholic beverage provided to the drinker already contains the bingeregulating agent.

In some embodiments, the binge regulating agent is taken-up first,before the alcoholic beverage is consumed. In the context of theseembodiments, the binge regulating agent is taken by the drinker(self-administered) about 15 minutes, about 20 minutes, about 30minutes, about 40 minutes, about 50 minutes, 60 minutes, 70 minutes, 80minutes, 90 minutes 120 minutes, 150 minutes, or about 180 minutes,before alcohol is consumed and any intermediate times there between.

In some embodiments, the binge regulating agent is taken-up subsequentlyfollowing alcohol consumption. In the context of these embodiments, thebinge regulating agent is taken by the drinker (self-administered) about5 minutes, about 7 minutes, about 10 minutes, about 15 minutes, about 20minutes, about 25 minutes, 30 minutes, about 35 minutes, about 40minutes or about 45 minutes, after the first or second or third orfourth drink, and any intermediate times there between. Preferably, thebinge regulating agent is consumed (e.g., self-administered) followingthe first or second drink.

Administration of an effective amount of the binge regulating agent asdescribed herein, whether alone or in combination with an alcoholicbeverage, to a subject will detectably reduce the amount of alcoholconsumed in a binge drinking, and will prevent many of the adverseaffects associated with excessive alcohol consumption particularlyshort-term effects such as heavy intoxication that leads to seriousconsequences such as accidents and uncontrolled violent behavior withsubsequent medical complications, as well as gastric irritation, anxietydisorders and other excitable states.

In some embodiments, administering the binge regulating agent to asubject (e.g., self-administering) yields a reduction in alcoholconsumption by at least about 10%, 20%, 30%, 50%, 60% or greater, up toabout 75-90%, or about 95% or greater. In some embodiments, thisreduction in alcohol consumption is during a single drinking sessionwhen the binge regulating agent is administered. In some embodiments,this reduction is during a period of time (e.g., a week), and may resultfrom administering the agent during every drinking session, or byreducing the occurrences of drinking sessions as a result of a single ormultiple administrations of the agent.

The effectiveness of mitigation of binge drinking can be measured inseveral ways. For example, subjects can self-report according toguidelines and procedures set up for such reporting. Objective measuresof alcohol consumption include the use of breath alcohol-meter readings,measuring serum CDT levels, and measuring serum γ-glutamyl transferase(GGT) levels. Urinary 5-HTOL may also be measured and is an indicator ofrecent alcohol consumption. 5-HTOL is a minor metabolite of 5-HT. Othersubjective and objective measures are also known. These measurements canbe taken or performed at various times before, during, and afterconsumption of the binge regulator.

The term “alcoholic beverage” as used herein encompasses any beveragehaving an alcoholic content of at least 2% by volume, whether distilled,fortified, brewed, or produced by fermentation, and includes, but is notlimited to, wine, beer, fermented liquids derived in whole or in partfrom fruit juices, such as cider and perry, spirits, flavored alcoholicbeverages collectively termed herein and in the art as “alcopops”, andthe like.

In some embodiments, the alcoholic beverage is an authentic beverage,for example, beer, wine, or any kind of spirit, that contains theoriginal amount of alcohol, for example, 5% by volume in beer, 13% inwine and 30% in a spirit. The term “wine” as used herein and in the artincludes the fermented juice of grapes, made in many varieties, such asred, white, sweet, dry, still, and sparkling. Exemplary wine beveragesinclude, but are not limited to, dry red or white wine, semi-dray red orwhite wine, rose wine, dessert wine, Port wine, Champagne, sparklingwine, and vermouth. Typical alcoholic wine beverages include analcoholic content of 10-14%.

Herein throughout, whenever a percentage (%) is indicated, volume % ofthe total volume of the beverage is meant, unless otherwise indicated.

The term “beer” as used herein and in the art means beverages obtainedby malting and fermenting some one or more of the cereal grains, andincludes ale, stout, porter and lager.

The term “spirit” as used herein and in the art refers to distilledalcohol beverages obtained, for example, by distilling starchy materialand include, but not limited to, variety of raw grain alcohols,brandies, liquors, saki, Ouzo, arrack, rum, vodka, tequila, schnapps,whiskey, gin, cordial, Cachaça, absinthe, baijiu, eau de vie, soju,aguardiente, palinka, fernet and slivovitz.

The binge regulating agent described herein can be administered togetherwith additional therapeutic agents administered as combination therapiesto treat alcohol-related disorders. The additional therapeutic agentsinclude, but are not limited to, traditional anti-alcohol agents and/orother agents as described herein above and known in the art, such asdisulfiram; naltrexone; acamprosate (Campral®); ondansetron; sertraline(Zoloft®); tiapride; gamma hydroxybutyrate (Alcover®); galanthamine;nalmefene (Revex); naloxone; benzodiazepines; neuroleptics such aslaevomepromazine (Neurocil®) and thioridazine (Melleril®); piracetam;clonidine; carbamazepine; clomethiazole (Distraneurin®); levetiracetam;quetiapine; risperidone; rimonabant; trazodone; topiramate;aripiprazole; amperozide; and modafinil.

The binge regulating agent as described herein for any one of themethods described herein and any embodiments thereof can also beadministered to a subject in combination with behavioral therapy orinteraction.

In some embodiments, binge mitigation is further supplemented byproviding to subjects a form of psychosocial intervention and/ormanagement, such as Brief Behavioral Compliance Enhancement Treatment(BBCET). BBCET, a standardized, manual-guided, brief (i.e., delivered inabout 15 minutes), psychosocial adherence enhancement procedure,emphasizes that medication/binge mitigation compliance is crucial tochanging participants' drinking behavior (Johnson et al., BriefBehavioral Compliance Enhancement Treatment (BBCET) manual. In: JohnsonB A, Ruiz P, Galanter M, eds. Handbook of clinical alcoholism treatment.Baltimore, Md.: Lippincott Williams & Wilkins; 2003, 282-301). Briefinterventions such as BBCET, have been shown to benefit treatment ofalcohol dependence. Psychosocial management regimens other than BBCETmay also be used, including, but not limited to, Cognitive BehavioralCoping Skills Therapy (CBT) (Project MATCH Research Group. MatchingAlcoholism Treatments to Client Heterogeneity: Project MATCHposttreatment drinking outcomes. J Stud Alcohol. 1997; 58:7-29),Motivational Enhancement Therapy (MET) (Project MATCH Research Group.Matching Alcoholism Treatments to Client Heterogeneity: Project MATCHposttreatment drinking outcomes. J. Stud. Alcohol. 1997, 58:7-29),Twelve-Step Facilitation Therapy (TSF) (Project MATCH Research Group.Matching Alcoholism Treatments to Client Heterogeneity: Project MATCHposttreatment drinking outcomes. J. Stud. Alcohol. 1997, 58:7-29),Combined Behavioral Intervention (CBI), (Anton et al., JAMA, 2006,295:2003-2017) Medical Management (MM) (Anton et al., JAMA, 2006,295:2003-2017), or the Biopsychosocial, Report, Empathy, Needs, Directadvice, and Assessment (BRENDA) model (Garbutt et al., JAMA, 2005,293:1617-1625). Alternative interventions such as hypnosis oracupuncture may also be employed together with binge mitigationdescribed herein in order to assist in treating an addictive alcoholuse.

Any one of the methods and uses described herein, including anyembodiments and combination thereof, utilize a compound represented byFormula I:

wherein:

each of R₁ and R₂ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₄)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl,aryl, heteroaryl, heteroalicyclic, —O(C₁-C₆)alkyl, OH, —OS(═O)₂CF₃,—OS(═O)₂—(C₁-C₆)alkyl, —S(═O)R₅, —CO₂R₅, —CONH₂, —CONR₅R₆, —COR₅, —CF₃,CN, —SRS, —SO₂NH₂, —SO₂NR₅R₆, —SO₂R₅, —OCO—(C₁-C₆)alkyl,—NCO—(C₁-C₆)alkyl, —CH₂O—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-OH, —CO-aryl,—NHSO₂-aryl, —NHSO₂—(C₁-C₁₅)alkyl, and halogen, or, alternatively, R₁and R₂ together with two or more of the phenyl carbon atoms form a—X₁—(CR₅R₆)_(m)—X₂— ring, wherein each of X₁ and X₂ is independentlyselected from C, O, NH or S and m is 1, 2, 3, or 4;

each of R₃ and R₄ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈) cycloalkyl, and—(CH₂)_(p)-thienyl, wherein p is 1, 2, 3, or 4, or alternatively, R₃ andR₄ are joined together to form a heterocylic ring (heteroalicyclic orheteroaryl) containing the nitrogen atom to which they are attached; and

each of R₅ and R₆ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl and aryl.

In some embodiments of the invention, the 2-aminoindan derivative of theFormula I is as presented herein, wherein R₁-R₆ are defined as follows:

each of R₁ and R₂ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl,aryl, —OCH₃, OH, —OSO₂CF₃, —OSO₂CH₃, —SORB, —CO₂R₅, —CONR₅R₆, —COR₅,—CF₃, —CN, —SRS, —SO₂NR₅R₆, —SO₂R₅, —CH₂—OH, halogen, phthalimidyl,thiophenyl, pyrrolyl, pyrrolinyl, and oxazolyl, or, alternatively, R₁and R₂ together with two or more of the phenyl carbon atoms form a—O(CH₂)_(m)O— ring, wherein m is 1 or 2;

R₃ and R₄ are joined together to form a heterocylic ring containing 4 to8 carbon atoms with the nitrogen atom to which they are attached; and

each of R₅ and R₆ is independently selected from the group consisting ofH, (C₁-C₈) alkyl, (C₂-C₈) alkenyl, and (C₃-C₈) cycloalkyl.

In some embodiments, the compound of Formula I is as described hereinwherein the amino group is a secondary or tertiary amine, namely atleast one of R₃ and R₄ is an alkyl, for example, propyl. Secondary (ortertiary) amino groups are preferred as the 2-aminoindan derivativescontaining a secondary (or tertiary) amine moiety are less susceptibleto enzymatic degradation by e.g., monoamine oxidase (MAO) enzymes andare thus more potent than primary amines when acting in the brain. Inaddition, secondary or tertiary amines are more hydrophobic and henceare more brain permeable.

In some embodiments, the compound of the Formula I is as describedherein, wherein R₁ and R₂ each independently is H, —OCH₃, or —OSO₂CF₃,or R₁ and R₂ together with two or more of the phenyl carbon atom form a—O(CH₂)_(m)O— ring, wherein m is 1 or 2.

Non-limiting examples of 2-aminoindan derivatives, which may be used inthe context of the present embodiments, include:

-   (1) 5-methoxy-2-aminoindan;-   (2) 5,6-dimethoxy-2-aminoindan;-   (3) 5-methoxy-2-(N-propylamino)indan;-   (4) 5,6-dimethoxy-2-(N-propylamino)indan;-   (5) 5,6-dimethoxy-2-(di-N-butylamino)indan;-   (6)    5-(trifluoromethylsulfonyloxy)-6-hydroxy-2-(di-N-propylamino)indan;-   (7) 5-(trifluoromethylsulfonyloxy)-2-(N-propylamino)indan;-   (8) 5,6-(di-trifluoromethylsulfonyloxy)-2-(N-propylamino)Indan;-   (9) 5,6-dimethoxy-2(pyrrolidino)indan;-   (10)    5-(trifluoromethylsulfonyloxy)-6-acetoxy-2-(di-N-propylamino)indan;-   (11)    5-trifluromethansulfonyloxy-6-methoxy-2-(di-N-propylamino)indan;-   (12) 5,6-ethylenedioxy-2-(di-N-propylamino)indan;-   (13) 5,6-methylenedioxy-2-(di-N-propylamino)indan;-   (14) 5-hydroxy-2-(n-propylamino)indan;-   (15) 5,6-dihydroxy-2-(n-propylamino)indan;-   (16) 4-methyl-2-aminoindan;-   (17) 4,5-di-methyl-2-aminoindan;-   (18) 5,6-di-methyl-2-aminoindan;-   (19) 6-methyl-2-aminoindan;-   (20) 4-fluoro-2-aminoindan;-   (21) 5-(i-propyl)-2-aminoindan;-   (22) 4,6-dimethyl-2-aminoindan;-   (23) 4,7-dimethyl-2-aminoindan;-   (24) 5-(t-butyl)-2-aminoindan;-   (25) 5-propyl-2-aminoindan;-   (26) 5-fluoro-2-(di-N-propylamino)indan;-   (27) 6-methylenedioxy-2-(di-N-propylamino)indan;-   (28) 5,6-dimethoxy-2(pyrrolidino)indan;-   (29) 5,6-(di-carbomethoxy)-2-(di-N-propylamino)indan;-   (30) 5-(carbomethoxy)-6-hydroxy-2-(di-N-propylamino)indan;-   (31) 5-bromo-2-(dipropylamino)indan;-   (32) (6-methylsulfanyl-indan-2-yl)-dipropyl-amine;-   (33) (6-methylsulfonyl-indan-2-yl)-dipropyl-amine;-   (34) (6-methylsulfinyl-indan-2-yl)-dipropyl-amine;-   (35) 2-dipropylamino-indan-5-carbaldehyde;-   (36) (5-iodo-indan-2-yl)-dipropyl-amine;-   (37) (4-iodo-indan-2-yl)-dipropyl-amine;-   (38) toluene-4-sulfonic acid 2-dipropylamino-indan-5-yl ester;-   (39) toluene-4-sulfonic acid 2-dipropylamino-6-hydroxy-indan-5-yl    ester;-   (40) N-[2-(benzyl-propylamino)-indan-5-yl]-4-methyl    benzene-sulfonamide;-   (41) N-[2-(benzyl-propyl-amino)-indan-5-yl]methanesulfonamide;-   (42) 2-[2-(benzyl-propyl-amino)-indan-5-yl]-isoindole-1,3-dione;-   (43) benzyl-propyl-(6-pyrrol-1-yl-indan-2-yl)-amine;-   (44) propyl-(6-pyrrol-1-yl-indan-2-yl)-amine;-   (45) propyl-(6-pyrrolidin-1-yl-indan-2-yl)-amine;-   (46) dipropyl-(6-pyrrolidin-1-yl-indan-2-yl)-amine;-   (47) cyclopropanecarboxylic    acid-[2-(benzyl-propyl-amino)-indan-5-yl]acetamide;-   (48) N-[2-(benzyl-propyl-amino)-indan-5-yl]propionamide;-   (49) N-[2-(benzyl-propyl-amino)-indan-5-yl]-2,2-dimethyl    propionamide;-   (50) 5-(2-propenyloxy)-2-(di-N-propylamino)-indan;-   (51) 5,6 di-toluenesulfonyloxy-2-(di-N-propylamino)indan;-   (52) 5-methanesulfonyloxy-2-(di-N-propylamino)indan;-   (53) 5-carbomethoxy-2-(di-N-propylamino)indan;-   (54) 5-carboxamido-2-(di-N-propylamino)indan;-   (55) 5,6-di-triluuomethansulfonyloxy-2-(propylamino)indan;-   (56) 4-methyl-2-(di-N-propylamino)indan;-   (57) 4,5-di-methyl-2-(di-N-propylamino)indan;-   (58) 5,6-di-methyl-2-(di-N-propylamino)indan;-   (59) 5-methyl-2-(di-N-propylamino)indan;-   (60) 4-fluoro-2-(N-propyl)aminoindan;-   (61) 5-(i-propyl)-2-(di-N-propylamino)indan;-   (62) 5-(i-propyl)-2-(N-propylamino)indan;-   (63) 4,6-dimethyl-2-(di-N-propylamino)indan;-   (64) 4,7-dimethyl-2-(di-N-propylamino)indan;-   (65) 5-propyl-2-(di-N-propylamino)indan;-   (66) 5-(t-butyl)-2-(dim-propylamino)indan;-   (67) 5-trifluoromethyl-2-(di-N-propylamino)indan;-   (68) 5-sulfoxamido-2-(di-N-propylamino)indan;-   (69) 5-(3-thiophene)-2-(di-N-propylamino)indan;-   (70) 5-ethynyl-2-(di-N-propylamino)indan;-   (71) 5-acetyl-2-(di-N-propylamino)indan;-   (72) 5-cyano-2-(di-N-propylamino)indan;-   (73) 5-carbomethoxy-6-acetoxy-2-(di-N-propylamino)indan;-   (74)    5-carbomethoxy-6-trifluoromethanesulfonyloxy-2-(di-N-propylamino)    indan;-   (75) 5-carbomethoxy-6-methoxy-2-(di-N-propylamino)indan;-   (76) 5-formyl-6-methoxy-2-(di-N-propylamino)indan;-   (77) 5-hydroxymethyl-6-methoxy-2-(di-N-propylamino)indan;-   (78) 5-carboxy-6-methoxy-2-(di-N-propylamino)indan;-   (79) 5-acetyl-6-methoxy-2-(di-N-propylamino)indan;-   (80) 5-carboxamido-6-methoxy-2-(di-N-propylamino)indan;-   (81) 5-ethynyl-6-methoxy-2-(di-N-propylamino)indan;-   (82) 5-cyano-6-methoxy-2-(di-N-propylamino)indan; and-   (83) 5,6-di-(hydroxmethyl-2-(di-N-propylamino)indan.

In some of any of the embodiments described herein, the 2-aminoindanderivative of Formula I is any one of the compounds (1)-(13) above, inwhich the phenyl moiety is substituted by one or two —OCH₃, or —OSO₂CF₃groups, or the phenyl moiety bears a —O(CH₂)_(m)O— ring, wherein m is 1or 2, fused thereto. The structural formulas of compounds 1-13 aredepicted in Table A hereinunder.

In exemplary embodiments, the 2-aminoindan derivative used is5-methoxy-2-aminoindan (Compound 1) or 5,6-dimethoxy-2-aminoindan(Compound 2), the chemical structures of which are depicted hereinbelow.

TABLE A Compound No. Name Structure  1 5-methoxy-2-aminoindan

 2 5,6-dimethoxy-2- aminoindan

 3 5-methoxy-2-(N- propylamino)indan

 4 5,6-dimethoxy-2-(N- propylamino)indan

 5 5,6-dimethoxy-2-(di-N- butylamino)indan

 6 5-(trifluoromethyl- sulfonyloxy)-6-hydroxy- 2-(di-N-propylamino)indan

 7 5-(trifluoromethyl- sulfonyloxy)-2-(N- propylamino)indan

 8 5,6-(di-trifluoromethyl- sulfonyloxy)-2-(N- propylamino)indan

 9 5,6-dimethoxy-2- (pyrrolidino)indan

10 5-(trifluoro- methylsulfonyloxy)- 6-acetoxy-2-(di-N-propylamino)indan

11 5-trifluoro- methansulfonyloxy- 6-methoxy-2-(di-N- propylamino)indan

12 5,6-ethylenedioxy-2-(di- N-propylamino)indan

13 5,6- methylenedioxy-2- (di-N- propylamino)indan

In any one of the embodiments described herein, each of the compoundsdescribed herein can further be in a form of a pharmaceuticallyacceptable salt thereof.

As used herein, the phrase “pharmaceutically acceptable salt” refers toa charged species of the parent compound and its counter-ion, which istypically used to modify the solubility characteristics of the parentcompound and/or to reduce any significant irritation to an organism bythe parent compound, while not abrogating the biological activity andproperties of the administered compound.

In the context of some of the present embodiments, a pharmaceuticallyacceptable salt of the compounds described herein may optionally be anacid addition salt comprising at least one basic (e.g., amine) group ofthe compound which is in a positively charged form (e.g., an ammoniumion), in combination with at least one counter-ion, derived from theselected acid, that forms a pharmaceutically acceptable salt.

The acid addition salts of the compounds described herein may thereforebe complexes formed between one or more basic groups of the drug and oneor more equivalents of an acid.

The acid addition salts may include a variety of organic and inorganicacids, such as, but not limited to, hydrochloric acid which affords ahydrochloric acid addition salt, hydrobromic acid which affords ahydrobromic acid addition salt, acetic acid which affords an acetic acidaddition salt, ascorbic acid which affords an ascorbic acid additionsalt, benzenesulfonic acid which affords a besylate addition salt,camphorsulfonic acid which affords a camphorsulfonic acid addition salt,citric acid which affords a citric acid addition salt, maleic acid whichaffords a maleic acid addition salt, malic acid which affords a malicacid addition salt, methanesulfonic acid which affords a methanesulfonicacid (mesylate) addition salt, naphthalenesulfonic acid which affords anaphthalenesulfonic acid addition salt, oxalic acid which affords anoxalic acid addition salt, phosphoric acid which affords a phosphoricacid addition salt, toluenesulfonic acid which affords ap-toluenesulfonic acid addition salt, succinic acid which affords asuccinic acid addition salt, sulfuric acid which affords a sulfuric acidaddition salt, tartaric acid which affords a tartaric acid addition saltand trifluoroacetic acid which affords a trifluoroacetic acid additionsalt. Each of these acid addition salts can be either a mono-additionsalt or a poly-addition salt, as these terms are defined herein.

In the context of some of the present embodiments, a pharmaceuticallyacceptable salt of the compounds described herein may optionally be abase addition salt comprising at least one group of the compound whichis in a form of an anion, in combination with at least one counter ion(i.e., cation) that forms a pharmaceutically acceptable salt. Examplesof suitable cations include metal cations of metals such as, but notlimited to, sodium, potassium, magnesium, and calcium or ammonium.

Each of these base addition salts can be either a mono-addition salt ora poly-addition salt, as these terms are defined herein.

Depending on the stoichiometric proportions between the basic or acidiccharged group(s) in the compound (e.g., amine group(s)) and thecounter-ion in the salt, the acid or base additions salts can be eithermono-addition salts or poly-addition salts.

The phrase “mono-addition salt”, as used herein, refers to a salt inwhich the stoichiometric ratio between the counter-ion and charged formof the compound is 1:1, such that the addition salt includes one molarequivalent of the counter-ion per one molar equivalent of the compound.

The phrase “poly-addition salt”, as used herein, refers to a salt inwhich the stoichiometric ratio between the counter-ion and the chargedform of the compound is greater than 1:1 and is, for example, 2:1, 3:1,4:1 and so on, such that the addition salt includes two or more molarequivalents of the counter-ion per one molar equivalent of the compound.

Further, in any one of the embodiments described herein, each of thecompounds described herein, including the salts thereof, can be in aform of a solvate or a hydrate thereof.

The term “solvate” refers to a complex of variable stoichiometry (e.g.,di-, tri-, tetra-, penta-, hexa-, and so on), which is formed by asolute (the 2-aminoindan derivatives described herein) and a solvent,whereby the solvent does not interfere with the biological activity ofthe solute.

The term “hydrate” refers to a solvate, as defined hereinabove, wherethe solvent is water.

The present embodiments further encompass any stereoisomers (enantiomersand diastereomers) of the compounds described herein, as well as anyisomorph thereof.

The compounds represented by Formula I as described herein may beprepared according to methods and practices known in the art, forexample, as taught in U.S. Pat. No. 5,708,018, which is incorporated byreference as if fully set forth herein.

According to an aspect of some embodiments of the present invention,there is provided a compound represented by Formula I as describedherein, in any one of the respective embodiments, and any combinationthereof, for use in regulating a binge behavior, as defined herein, orin the manufacture of a medicament for regulating a binge behavior asdescribed herein.

According to an aspect of some embodiments of the present invention,there is provided a compound represented by Formula I as describedherein, in any one of the respective embodiments, and any combinationthereof, for use in reducing a consumption of an alcoholic beverage, asdefined herein, or in the manufacture of a medicament for reducing aconsumption of an alcoholic beverage, as described herein.

In any one of the methods and uses described herein, including any oneof embodiments thereof, the compound of Formula I described herein mayform a part of a composition, which further comprises a pharmaceuticallyacceptable carrier, and in some embodiments, the composition is for usein a method of regulating binge behavior, for example binge drinking, orregulating alcohol consumption for example excessive alcoholconsumption, as defined herein.

Pharmaceutical compositions comprising the compound of Formula I asdescribed herein, may be administered systemically in oral solid or oralliquid formulations, or as suppository, aerosol, topical or othersimilar formulations. In preferred embodiments, the binge regulator or acomposition comprising same is administered to a subject orally.

An aspect of some embodiments of the present invention relates to thepreparation of pharmaceutical compositions comprising a derivative of2-aminoindan useful for regulating a binge behavior as described herein.

In addition to a derivative of 2-aminoindan as an active ingredient,such pharmaceutical compositions may contain one or morepharmaceutically-acceptable carriers and other ingredients known toenhance and facilitate drug administration.

The active ingredient may be present in the pharmaceutical compositionin the form of a physiologically acceptable ester or salt, such as incombination with a physiologically acceptable cation or anion, asdescribed herein above and is well known in the art.

A pharmaceutical composition of the invention may be prepared, packaged,or sold as a free-flowing powder, a tablet, a capsule, a lozenge, aliquid, a liquid concentrate or a syrup.

In some embodiments, the pharmaceutical composition prepared, packaged,or sold in bulk, as a single unit dose, or as a plurality of single unitdoses. In preferred embodiments, the composition is a unit dosage formcomposition.

As used herein, a “unit dosage form” is a discrete amount of thepharmaceutical composition comprising a predetermined amount of theactive ingredient, herein a binge regulating agent represented byFormula I as described herein. The amount of the active ingredient isgenerally equal to the dosage of the active ingredient which would beadministered to a subject, or a convenient fraction of such a dosagesuch as, for example, one-half or one-third of such a dosage.

Controlled- or sustained-release formulations of a pharmaceuticalcomposition described herein may be made using conventional technology.

The formulations of the pharmaceutical compositions described herein maybe prepared by any method known or hereafter developed in the art ofpharmacology. In general, such preparatory methods include the step ofbringing the active ingredient into association with a carrier or one ormore other accessory ingredients, and then, if necessary or desirable,shaping or packaging the product into a desired single- or multi-doseunit.

A formulation of a pharmaceutical composition suitable for oraladministration may be prepared, packaged, or sold in the form of adiscrete solid dose unit including, but not limited to, a tablet, a hardor soft capsule, a cachet, a troche, or a lozenge, each containing apredetermined amount of the active ingredient. Other formulationssuitable for oral administration include, but are not limited to, apowdered or granular formulation, an aqueous or oily suspension, anaqueous or oily solution, or an emulsion.

As used herein, an “oily” liquid is one which comprises acarbon-containing liquid molecule and which exhibits a less polarcharacter than water.

A tablet comprising the active ingredient may, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets may be prepared bycompressing, in a suitable device, the active ingredient in afree-flowing form such as a powder or granular preparation, optionallymixed with one or more of a binder, a lubricant, an excipient, a surfaceactive agent, and a dispersing agent. Molded tablets may be made bymolding, in a suitable device, a mixture of the active ingredient, apharmaceutically acceptable carrier, and at least sufficient liquid tomoisten the mixture. Pharmaceutically acceptable excipients used in themanufacture of tablets include, but are not limited to, inert diluents,granulating and disintegrating agents, binding agents, and lubricatingagents. Dispersing agents include, but are not limited to, potato starchand sodium starch glycollate. Surface active agents include, but are notlimited to, sodium lauryl sulphate. Diluents include, but are notlimited to, calcium carbonate, sodium carbonate, lactose,microcrystalline cellulose, calcium phosphate, calcium hydrogenphosphate, and sodium phosphate. Known granulating and disintegratingagents include, but are not limited to, corn starch and alginic acid.Known binding agents include, but are not limited to, gelatin, acacia,pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropylmethylcellulose. Known lubricating agents include, but are not limitedto, magnesium stearate, stearic acid, silica, and talc.

Tablets may be non-coated or may be coated using known methods toachieve delayed disintegration in the gastrointestinal tract of asubject, thereby providing sustained release and absorption of theactive ingredient. By way of example, a material such as glycerylmonostearate or glyceryl distearate may be used to coat tablets. Furtherby way of example, tablets may be coated using methods described in U.S.Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to formosmotically-controlled release tablets.

Tablets may further comprise a sweetening agent, a flavoring agent, acoloring agent, a preservative, or some combination of these in order toprovide pharmaceutically elegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using aphysiologically degradable composition, such as gelatin. Such hardcapsules comprise the active ingredient, and may further compriseadditional ingredients including, for example, an inert solid diluentsuch as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made usinga physiologically degradable composition, such as gelatin. Such softcapsules comprise the active ingredient, which may be mixed with wateror an oil medium such as peanut oil, liquid paraffin, or olive oil.

Lactulose can also be used as a freely erodible filler and is usefulwhen the binge regulator are prepared in capsule form.

Liquid formulations of a binge regulator, which are suitable for oraladministration may be prepared, packaged, and sold either in liquid formor in the form of a dry product intended for reconstitution with water,an alcoholic beverage or another suitable vehicle prior to use.

Liquid suspensions may be prepared using conventional methods to achievesuspension of the active ingredient in an aqueous or oily vehicle.Aqueous vehicles include, for example, water and isotonic saline. Oilyvehicles include, for example, almond oil, oily esters, ethyl alcohol,vegetable oils such as arachis, olive, sesame, or coconut oil,fractionated vegetable oils, and mineral oils such as liquid paraffin.Liquid suspensions may further comprise one or more additionalingredients including, but not limited to, suspending agents, dispersingor wetting agents, emulsifying agents, demulcents, preservatives,buffers, salts, flavorings, coloring agents, and sweetening agents. Oilysuspensions may further comprise a thickening agent.

Known suspending agents include, but are not limited to, sorbitol syrup,hydrogenated edible fats, sodium alginate, polyvinylpyrrolidone, gumtragacanth, gum acacia, and cellulose derivatives such as sodiumcarboxymethylcellulose, methylcellulose, andhydroxypropylmethylcellulose.

Known dispersing or wetting agents include, but are not limited to,naturally occurring phosphatides such as lecithin, condensation productsof an alkylene oxide with a fatty acid, with a long chain aliphaticalcohol, with a partial ester derived from a fatty acid and a hexitol,or with a partial ester derived from a fatty acid and a hexitolanhydride (e.g., polyoxyethylene stearate, heptadecaethyleneoxycetanol,polyoxyethylene sorbitol monooleate, and polyoxyethylene sorbitanmonooleate, respectively).

Known emulsifying agents include, but are not limited to, lecithin andacacia. Known preservatives include, but are not limited to, methyl,ethyl, or n-propyl para hydroxybenzoates, ascorbic acid, and sorbicacid. Known sweetening agents include, for example, glycerol, propyleneglycol, sorbitol, sucrose, and saccharin. Known thickening agents foroily suspensions include, for example, beeswax, hard paraffin, and cetylalcohol.

In some embodiments, a preparation comprising the binge mitigation agentis in the form of a syrup or elixir or for administration in the form ofdrops, and may comprise active ingredients optionally together with asweetener, which is preferably calorie-free, and which may furtherinclude methylparaben or propylparaben as antiseptics, a flavoring and asuitable color.

Liquid solutions of the active ingredient in aqueous or oily solventsmay be prepared in substantially the same manner as liquid suspensions,the primary difference being that the active ingredient is dissolved,rather than suspended in the solvent. Liquid solutions of thepharmaceutical composition described herein may comprise each of thecomponents described herein above with regard to liquid suspensions, itbeing understood that suspending agents will not necessarily aiddissolution of the active ingredient in the solvent. Aqueous solventsinclude, for example, water and isotonic saline. Oily solvents include,for example, almond oil, oily esters, ethyl alcohol, vegetable oils suchas arachis, olive, sesame, or coconut oil, fractionated vegetable oils,and mineral oils such as liquid paraffin.

Powdered and granular formulations of a binge regulating agent describedherein may be prepared using known methods. Such formulations may beused, for example, to form tablets, to fill capsules, or to prepare anaqueous or oily suspension or solution by addition of an aqueous or oilyvehicle thereto. Each of these formulations may further comprise one ormore of a dispersing or wetting agent, a suspending agent, and apreservative as described herein. Additional excipients, such as fillersand sweetening, flavoring, or coloring agents, may also be included inthese formulations.

A pharmaceutical composition comprising at least one binge mitigationagent as described herein may be prepared, packaged, or sold in aformulation suitable for buccal administration. Such formulations may,for example, be in the form of tablets or lozenges made usingconventional methods, and may, for example, comprise about 0.1% to about20% (w/w) active ingredient, the balance comprising an orallydissolvable or degradable composition and, optionally, one or more ofthe additional ingredients described herein. Alternatively, formulationssuitable for buccal administration may comprise a powder or anaerosolized or atomized solution or suspension comprising the activeingredient. Such powdered, aerosolized, or atomized formulations, whendispersed, preferably have an average particle or droplet size in therange from about 0.1 to about 200 nanometers, and may further compriseone or more of the additional ingredients described herein.

A pharmaceutical composition comprising at least one anti bingeing agentmay be prepared, packaged, or sold in a formulation suitable forintramucosal administration. Intramucosal administration of bingemitigators allows passage or absorption of the active agents acrossmucosa. Such type of administration is useful for absorption orally(gingival, sublingual, buccal, etc.), rectally, vaginally, pulmonary,nasally, etc.

In some embodiments, the pharmaceutical composition described herein isapplied via sublingual administration. This route of administration iscapable of producing a rapid onset of action due to the considerablepermeability and vascularization of the buccal mucosa. Moreover,sublingual administration can also allow the administration of activeingredients, in cases where they are not normally absorbed at the levelof the stomach mucosa or digestive mucosa after oral administration, oralternatively in cases where they are partially or completely degradedin acidic medium after ingestion of, for example, a tablet.

Sublingual tablets are usually prepared by direct compression of amixture of powders comprising the active ingredient and excipients forcompression, such as diluents, binders, disintegrating agents andadjuvants. In an alternative method of preparation, the activeingredient and the compression excipients can be dry- or wet-granulatedbeforehand.

As used herein, “additional ingredients” include, but are not limitedto, one or more of the following: excipients; surface active agents;dispersing agents; inert diluents; granulating and disintegratingagents; binding agents; lubricating agents; sweetening agents; flavoringagents; coloring agents; preservatives; physiologically degradablecompositions such as gelatin; aqueous vehicles and solvents; oilyvehicles and solvents; suspending agents; dispersing or wetting agents;emulsifying agents, demulcents; buffers; salts; thickening agents;fillers; emulsifying agents; antioxidants; antibiotics; antifungalagents; stabilizing agents; and pharmaceutically acceptable polymeric orhydrophobic materials. Other “additional ingredients” which may beincluded in the pharmaceutical compositions of the invention are knownin the art and described, for example in Genaro, ed., 1985, Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa., which isincorporated herein by reference.

The phrases “flavoring agent” and “odoriferous agent”, as used herein,describe a class of substances which are added to edible products inorder to induce a certain flavor or smell in the product, and arecommonly referred to also as “flavorants”. Flavorants can be syntheticor natural extracts, which are extracted from a source substance.Typical flavorants are specific and often complex mixtures of singularnaturally occurring or synthetic flavor compounds combined together toeither imitate or enhance a natural flavor. Many flavorants are esters,which can be characterized by a typical flavor, such as, for somenon-limiting examples, diacetyl which gives a buttery flavor, isoamylacetate that is perceived as banana, cinnamic aldehyde which is thebasis for the typical flavor of cinnamon, ethyl propionate is perceivedas fruity, limonene is perceived as orange, ethyl-(E,Z)-2,4-decadienoate is perceived as pear, allyl hexanoate is perceivedas pineapple, ethyl maltol, is perceived as sugar or cotton candy,methyl salicylate is known as the wintergreen flavor, and benzaldehydeis perceived as bitter almond.

In some embodiments, the flavoring agent used is of a natural source andcan be, for example, an extract of a fruit, a vegetable, a herb or ofany other edible substance, a fruit juice or a vegetable juice, or anycombination thereof. Such natural flavoring agents are often consideredalso as providing an added nutritional value to an alcohol-substitutebeverage containing same.

The terms “color agent” or “colorant”, as used herein, refers to anynatural or synthetic coloring substance, and describes any substancethat is added to food or drink in order to alter its color. Exemplaryusable colorants include, but are not limited to, synthetic colorantssuch as FD&C Blue No. 1—Brilliant Blue FCF (E133), FD&C Blue No.2—Indigotine (E132), FD&C Green No. 3—Fast Green FCF (E143), FD&C RedNo. 40—Allura Red AC (E129), FD&C Red No. 3—erythrosine (E127), FD&CYellow No. 5—tartrazine (E102), and FD&C Yellow No. 6—Sunset Yellow FCF(E110), and natural food colorants such as carmine (E120), enocianin(E163), black carrot (E163), paprika (E160c), annatto (E160b), betacarotene (E160a), lutein (E161b), riboflavin (E101), curcumin (E100),copper chlorophyllin (E141), chlorophyll (E140), caramel (E150), andextracts of foodstuffs such as elderberry, aronia, grape, beetroot,carrot, turmeric (tumeric) root, spinach, stinging nettle and burntsugar (caramelized sugar).

The term “preservative”, as used herein, describes a synthetic ornatural additive substance that is added to edible products in order toprevent or retard chemical and biochemical decomposition of the productby oxygen, moisture and/or microbes. Exemplary anti-microbialpreservatives include, but are not limited to, calcium propionate,sodium nitrate, sodium nitrite, sulfites (sulfur dioxide, sodiumbisulfite, potassium hydrogen sulfite, etc.) and disodium EDTA, sodiumbenzoate, potassium sorbate. Natural substances that retardmicroorganisms growth include lactic acid, salt, sugar and vinegar.

Exemplary antioxidant preservatives include, but are not limited to,butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).Natural antioxidants include, but are not limited to, herbal extractssuch as rosemary and oregano, and vitamins such as Vitamin E and VitaminC (ascorbic acid).

The phrase “foaming agent”, as used herein, describes an ediblesurfactant, which when present in small amounts, facilitates theformation of a foam, or enhances its colloidal stability by inhibitingthe coalescence of bubbles. Exemplary foaming agents include, withoutlimitation, sodium laureth/lauryl sulfate (SLS), sodium lauryl ethersulfate (SLES) and ammonium lauryl sulfate (ALS).

The phrase “antifoaming agent”, as used herein, describes an ediblesubstance that inhibits the formation of foam and curbs effusion oreffervescence in edible products. An exemplary antifoaming agent ispolydimethylsiloxane.

The phrases “viscosity modifying agent” or “thickener” as used hereinare interchangeable and describe agents that enables to control theviscosity of the beverages described herein. Exemplary thickenersinclude, but are not limited to, starch-based thickeners such asmaltodextrin and gum-based thickeners such as xanthan or cellulose gum.

It is expected that during the life of a patent maturing from thisapplication many relevant binge behaviors and binge regulators (otherthan the aminoindan derivatives described herein) will be developed andthe scope of the terms “binge” and “binge regulator” is intended toinclude all such new technologies a priori. Whenever a numerical rangeis indicated herein, it is meant to include any cited numeral(fractional or integral) within the indicated range. The phrases“ranging/ranges between” a first indicate number and a second indicatenumber and “ranging/ranges from” a first indicate number “to” a secondindicate number are used herein interchangeably and are meant to includethe first and second indicated numbers and all the fractional andintegral numerals therebetween.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “10 μm” is intended to mean“about 10 μm”.

As used herein, numerical ranges preceded by the term “about” should notbe considered to be limited to the recited range. Rather, numericalranges preceded by the term “about” should be understood to include arange accepted by those skilled in the art for any given element inmicrocapsules or formulations according to the present invention.

The term “about” as used herein means within an acceptable error rangefor a particular value as determined by one of ordinary skill in theart, which will depend in part on how the value is measured ordetermined, i.e., the limitations of the measurement system. Forexample, “about” can mean a range of up to 10%, more preferably up to5%, and still more preferably up to 1% of a given value. Whereparticular values are described in the application and claims, unlessotherwise stated, the meaning of the term “about” is within anacceptable error range for the particular value.

The terms “comprises”, “comprising”, “includes”, “including”, “having”and their conjugates mean “including but not limited to”.

The term “consisting of” means “including and limited to”.

The term “consisting essentially of” means that the composition, methodor microcapsules may include additional ingredients, steps and/or parts,but only if the additional ingredients, steps and/or parts do notmaterially alter the basic and novel characteristics of the claimedcomposition, method or structure.

As used herein, the singular form “a”, “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” may include a pluralityof compounds, including mixtures thereof.

As used herein the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, techniques and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

As used herein, the term “alkyl” refers to a saturated aliphatichydrocarbon including straight chain and branched chain groups.Preferably, the alkyl group has 1 to 20 carbon atoms. Whenever anumerical range; e.g., “1-20”, is stated herein, it implies that thegroup, in this case the alkyl group, may contain 1 carbon atom, 2 carbonatoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. Morepreferably, the alkyl is a medium size alkyl having 1 to 10 or 1 to 8carbon atoms. Most preferably, unless otherwise indicated, the alkyl isa lower alkyl having 1 to 8 carbon atoms.

An “alkenyl” group refers to a partially unsaturated hydrocarbonincluding straight chain and branched chain groups, which consists of atleast two carbon atoms and at least one carbon-carbon double bond.Preferably, the alkenyl is a medium size alkenyl having 2 to 10 or 2 to8 carbon atoms. Most preferably, unless otherwise indicated, the alkenylis a lower alkenyl having 2 to 4 carbon atoms. Non-limiting examples ofalkenyl include ethenyl (vinyl), propenyl, butenyl, pentenyl andhexenyl.

An “alkynyl” group refers to an a partially unsaturated hydrocarbonincluding straight chain and branched chain groups, which consists of atleast two carbon atoms and at least one carbon-carbon triple bond.Preferably, the alkynyl is a medium size alkynyl having 2 to 10 or 2 to8 carbon atoms. Most preferably, unless otherwise indicated, the alkynylis a lower alkynyl having 2 to 8 carbon atoms. Non-limiting examples ofalkynyl include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

A “cycloalkyl” group refers to a saturated, all-carbon monocyclic orpolycyclic (fused ring, i.e., rings which share an adjacent pair ofcarbon atoms) group, having 3 to 20, preferably 3 to 8 carbon atoms.Examples, without limitation, of cycloalkyl groups are cyclopropane,cyclobutane, cyclopentane, cyclohexane and cycloheptane.

An “aryl” group refers to an all-carbon monocyclic or polycyclic(fused-ring i.e., rings which share adjacent pairs of carbon atoms)groups having a completely conjugated pi-electron system. Examples,without limitation, of aryl groups are phenyl, naphthalenyl andanthracenyl.

A “heteroaryl” group, as used herein, refers to a monocyclic orpolycyclic (fused ring, i.e., rings which share an adjacent pair ofatoms) group having in the ring(s) one or more heteroatoms, selectedfrom nitrogen, oxygen and sulfur and, in addition, having a completelyconjugated pi-electron system. Examples, without limitation, ofheteroaryl groups include pyrrole, furan, thiophene, imidazole, oxazole,thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline,phthalimide, and purine.

A “heteroalicyclic” group as used herein refers to a monocyclic orpolycylic (namely, a fused ring group as defined herein) having in thering(s) one or more atoms such as nitrogen, oxygen and sulfur. The ringsmay also have one or more double bonds. However, the rings do not have acompletely conjugated pi-electron system. Representative examples arepiperidine, piperazine, tetrahydro furane, tetrahydropyrane, morpholino,pyrroline and the like.

As used herein, the term “hydroxyalkyl” refers to an alkyl, as this termis defined herein, substituted by an OH group, and includes, forexample, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxy-n-butyl.

As used herein the term thienyl refers to the radical:

As used herein, the term “halogen”, which is also referred to hereininterchangeably as “halo”, includes chloro (Cl), bromo (Br), iodo (I)and fluoro (F).

Any of the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl,heteroclicylic or aryl group as defined herein may be substituted orunsubstituted. When substituted, the substituent group can be, forexample, alkyl, —O—(C₁-C₈)alkyl, —O—(C₃-C₈)cycloalkyl, trihaloalkyl,hydroxyalkyl, (C₃-C₈) cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl,heteroalicyclic, halo, OH, O-aryl, —SH, —S—(C₁-C₈)alkyl,—S—(C₃-C₈)cycloalkyl, —S-aryl, —O—S═O, —S(═O)₂—R′, —CN, —NO₂,—O—P(═O)(OR′)(OR″), —PR′R″, —C(═O)—R′, —C(═S)—R′, —C(═O)—O—R′,—C(═S)—O—R′, —OC(═O)—NR′R″, —OC(═S)—NR′R″, —OC(═S)—NR′R″, —S(═O)₂—NR′R″,and —NR′R″, where R′ and R″, each independently, is hydrogen, alkyl,alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) orheteroalicyclic (bonded through a ring carbon), as these terms aredefined herein.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination or as suitable in any other describedembodiment of the invention. Certain features described in the contextof various embodiments are not to be considered essential features ofthose embodiments, unless the embodiment is inoperative without thoseelements.

Various embodiments and aspects of the present invention as delineatedhereinabove and as claimed in the claims section below find experimentalsupport in the following examples.

EXAMPLES

Reference is now made to the following examples, which together with theabove descriptions illustrate some embodiments of the invention in a nonlimiting fashion.

Example 1 Regulating Binge Drinking During a Drinking Session

Unit dosage forms each comprising 80 mg of Compound 1 and/or Compound 2as described herein, in gelatin capsules (size “1), are prepared.

A capsule is swallowed at the beginning of a drinking session with eachalcoholic drink. Volunteers are asked about their drinking habits atboth the beginning and end of a drinking session. At the end of thesession they are also asked if their alcohol consumption changed due tothe consumption of the binge mitigating agent. Then, the volunteers areasked if they would repeat the process of their own free will if themitigating agent was readily accessible (for example, sold with alcoholor as a pill over the counter).

In an exemplary study, volunteers reported a substantial reduction(e.g., of at least 30%) in alcohol consumption during the drinkingsession.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting. In addition, any priority document(s) of this applicationis/are hereby incorporated herein by reference in its/their entirety.

What is claimed is:
 1. A method of regulating binge behavior, the methodcomprising administrating to a subject in need thereof a compoundrepresented by Formula I:

wherein: each of R₁ and R₂ is independently selected from the groupconsisting of H, (C₁-C₈)alkyl, (C₂-C₄)alkenyl, (C₂-C₈)alkynyl,(C₃-C₈)cycloalkyl, aryl, heteroaryl, heteroalicyclic, —O(C₁-C₆)alkyl,OH, —OS(═O)₂CF₃, —OS(═O)₂—(C₁-C₆)alkyl, —S(═O)R₅, —CO₂R₅, —CONR₅R₆,—COR₅, —CF₃, CN, —SR₅, —SO₂NR₅R₆, —SO₂R₅, —OCO—(C₁-C₆)alkyl,—NCO—(C₁-C₆)alkyl, —CH₂O—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-OH, and halogen,or, alternatively, R₁ and R₂ together with two or more of the phenylcarbon atoms form a X₁—(CR₅R₆)_(m)—X₂— ring, wherein each of X₁ and X₂is independently selected from O, NH or S and m is 1, 2, 3, or 4; eachof R₃ and R₄ is independently selected from the group consisting of H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈) cycloalkyl, and—(CH₂)_(p)-thienyl, wherein p is 1, 2, 3, or 4, or alternatively, R₃ andR₄ are joined together to form a heterocylic ring (heteroalicyclic orheteroaryl) containing the nitrogen atom to which they are attached; andeach of R₅ and R₆ is independently selected from the group consisting ofH, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₃-C₈)cycloalkyl and aryl, therebyregulating the binge behavior, wherein at least one of R₃ and R₄ is H,and wherein the compound of Formula I is selected from:5-methoxy-2-aminoindan; 5,6-dimethoxy-2-aminoindan;5-methoxy-2-(N-propylamino)indan; 5,6-dimethoxy-2-(N-propylamino)indan;5-(trifluoromethylsulfonyloxy)-2-(N-propylamino)indan;5,6-(di-trifluoromethylsulfonyloxy)-2-(N-propylamino)Indan; and5,6-dimethoxy-2(pyrrolidino)indan.
 2. The method of claim 1, whereinsaid binge behavior is associated with alcohol consumption, eating,tobacco consumption, shopping or sexual conduct.
 3. The method of claim2, wherein said binge behavior is binge drinking.
 4. The method of claim1, wherein said compound forms a part of a composition, which furthercomprises a pharmaceutically acceptable carrier.
 5. The method of claim4, wherein said composition is in a form of a free-flowing powder, atablet, a capsule, a lozenge, a liquid, a liquid concentrate or a syrup.6. The method of claim 4, wherein said composition is a unit dosage formcomposition.
 7. The method of claim 6, wherein an amount of saidcompound in said unit dosage form ranges from 30 mg to 130 mg.
 8. Themethod of claim 7, wherein said amount of said compound is 70 mg.
 9. Themethod of claim 1, wherein said compound or composition is administeredto a subject orally.
 10. The method of claim 1, wherein the compound ofFormula I is 5-methoxy-2-aminoindan.
 11. A pharmaceutical compositioncomprising 5-methoxy-2-aminoindan, the composition being formulated fororal administration, and being a liquid unit dosage form composition.12. The pharmaceutical composition of claim 11, being packaged as asingle unit dose or as a plurality of single unit doses.
 13. Thepharmaceutical composition of claim 11, wherein said unit dosage formcomprises from 30 mg to 130 mg of said compound.